Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal autoimmune skin blistering diseases. While PV is characterized by suprabasilar blisters and IgG autoantibodies against desmoglein 3 (Dsg3), PF is characterized by subcorneal blisters and autoantibodies to Dsg1. The pathogenicity of PV and PF autoantibodies has been demonstrated by IgG passive transfer mouse models. However, the mechanism by which PF and PV autoantibodies cause epidermal blistering is not fully understood. The overall goal of our study is to understand the mode of action of pemphigus autoantibodies in causing skin blistering in an effort to generate new knowledge that may be beneficial in the development of better therapies for these diseases. Our central hypothesis is that proteolysis is involved in the pathogenic cascade of pemphigus, and that matrix metalloproteinase 2 (MMP2) plays a critical role in the final stage of epidermal blister formation via proteolytic cleavage of key adhesive molecules of keratinocytes. This hypothesis is based on our novel observations that pharmacologic and genetic blockade of MMP2 protects mice against experimental pemphigus. We propose three specific aims to test our hypothesis. Aim 1 is to extend our preliminary studies on the critical role of MMP2 in the induction of experimental pemphigus. Aim 2 is to demonstrate the upregulation and activation of MMP2 in the skin of model mice and pemphigus patients. Aim 3 is to investigate how MMP2 contributes to pemphigus blister formation. The findings from this proposal should significantly increase our understanding of the disease pathology and identify new therapeutic target for these diseases. PUBLIC HEALTH RELEVANCE: Pemphigus is a group of life-threatening autoimmune blistering diseases characterized by pathogenic autoantibodies that target epidermal desmogleins and cause skin blisters. The pathogenic mechanisms underlying how pemphigus autoantibodies lead to skin injury are not fully elucidated. In this application, we propose to investigate the role of proteinases in pemphigus skin blistering. The findings from this study should increase our understanding of the disease pathology and may lead to development of new treatments for the disease.